The manufacture of many classes of products requires precisely controlled chemical environments characterized by stringent criteria on the acceptable levels of particulate and/or gas phase contaminants. Semiconductor and microelectronics processing, for example, requires very low levels of molecular and particulate contaminants to provide high purity materials and processing conditions enabling a wide range of state of the art products. Similarly, the manufacture of pharmaceutical and biological products requires highly sterile environments characterized by low levels of biologically active contaminants to address safety and efficacy considerations.
Currently, the electronic manufacturing industry relies primarily on filtration for removal of particulate to maintain cleanroom conditions. Filtration is typically achieved by pumping ambient gas through either a high efficiency particulate air (HEPA) or an ultra-low penetration air (ULPA) filtration system. HEPA and ULPA filtration are capable of achieving low particulate levels but require a substantial pressure drop to transport gas through the dense filters necessary for effective particulate collection. Additionally, current HEPA and ULPA filtration systems remove almost no airborne molecular contamination (AMC), such as volatile organic compounds (VOCs). The VOCs can lead to surface molecular contaminations, such as residues, within the electronics, which may substantially impact physical, chemical, electrical, or optical performance. As a result, it is necessary for some semiconductor and microprocessing applications to implement chemical filtration to effectively reduce the concentration of AMC, which introduces additional cost, pressure drop and uncertainty regarding filter performance over time.
The pharmaceutical industry also must ensure that chemical composition of manufacturing and handling environments are precisely controlled. Currently, aseptic environments for the manufacture of pharmaceutical and biological products are typically achieved by a combination of filtration and sterilization processes. Filtration, as in the electronic manufacturing industry, relies on HEPA or ULPA filtration systems. Sterilization is typically achieved by treating the enclosure with one or more gas-phase sterilants, such as vaporized hydrogen peroxide (VHP), formaldehyde or chlorine dioxide. Filtration is continuous and compatible with typical operation conditions of the enclosure, whereas sterilization requires the enclosure to cease operation while the gas-phase sterilant is present.
The highest current standard for aseptic pharmaceutical manufacturing is Grade A and ISO Class 5 which requires a particulate contamination level below 3520 particulates per cubic meter at 0.5 μm and less than 1 colony forming unit (CFU) per cubic meter. Particulate contamination is typically continuously monitored during production using suitable instrumentation, such as an optical particle counter. Biological contamination is typically monitored using growth-based culture methods requiring samples to be taken using settling plates or impactors provided within the enclosure over specified time intervals and subsequently monitored for bacterial growth. Under standard culture protocols, bacterial growth may not appear for 24 hours or longer after exposure, thus requiring any pharmaceutical made or tested within the enclosure to be stored while bacteria is allowed to grow and environmental monitoring data reviewed before the product is released for shipment. If sufficient bacteria are identified in culture, pharmaceutical products corresponding to a relevant time period may need to be destroyed and the enclosure decontaminated.
While HEPA filtration combined with gas sterilization is capable of meeting Grade A and ISO Class 5 standards these techniques are susceptible to certain practical issues limiting the ability to efficiently control and maintain aseptic conditions. First, conventional HEPA filtration methods are unable to remove some viruses having small physical dimensions (e.g., <0.2 μm) and conventional methods for sterility assurance, such as growth-based culture methods, do not effectively detect some viruses that require living cells to replicate. Accordingly, reliance on HEPA filtering alone may raise the potential for viral contamination that is difficult to assess using conventional sterility assurance methods. Second, trapped microbial contaminants within HEPA filters can develop into a biofilm, thereby compromising the sterility of filter processing. For example, some biofilm are extended, microbial colonies which eventually enter a dispersion phase in which individual cells break free and seek to replicate on other surfaces potentially contaminating an aseptic environment between sterilizations. Third, there is a risk that trapped microorganisms that are difficult to detect may become liberated from a HEPA filter over time. For example, some individual bacterial spores do not form colonies while in a weakened state but are considered viable but non-culturable. In addition, some vegetative bacterial or fungal cells will not form colonies on standard agar growth-culture media and, thus, will also go undetected via sterilization assurance monitoring. These problems present significant risks of undetected contamination and therefore, cleanroom management commonly employs frequent decontamination using gas-phase sterilants to ensure sterile conditions.
Gas-phase sterilants are very effective at deactivating biological contaminants. However, a drawback of using a gas-phase sterilant is that the after an enclosure is treated (the decontamination phase) the enclosure must be aerated for a period of time to reduce the concentration the gas-phase sterilant (the aeration phase) to a human exposure limit. After sterilization with VHP, for example, enclosures are typically aerated for 4-5 hours in order to reduce the concentration of VHP to the human exposure limit of 1 part per million. Moreover, new protocols for VHP decontamination for certain applications require aeration to continue until a 10 part per billion concentration of VHP is reached, thus requiring 8-9 hours. As the enclosure cannot be used for production during the aeration phase, such aseptic processes directly impact overall throughput and productivity. Thus, managing enclosure sterility presents a practical tradeoff as to the extent and frequency of aseptic decontamination cycles which impact throughput and the risk of contamination and associated costly destruction of potentially contaminated products.
As will be understood from the foregoing, there remains a need in the art for processing systems and methods capable of achieving efficient filtration and processing of cleanroom enclosures. For example, processing systems and methods are needed for cleanroom and manufacturing applications that provide effective inactivation and removal of biological particles or for the degradation of process gases, such as sterilants, or molecular contaminants, such as VOCs. In addition, aseptic processing systems are needed for cleanroom and manufacturing applications that decrease the frequency and non-productive time required for process gas and gas-phase sterilant decontamination processing, for example, by decreasing the time an enclosure cannot be used due to the presence of process gas or gas-phase sterilant present, for example, during aeration phase.